T-cell derived interferon-gamma contributes to arteriolar dysfunction during acute hypercholesterolemia.

OBJECTIVES T-lymphocytes and interferon-gamma (IFN-gamma) contribute to leukocyte recruitment in postcapillary venules during hypercholesterolemia. Our objectives were to determine whether: (1) T-lymphocytes are the source of this IFN-gamma, and (2) whether T-cell-derived IFN-gamma also mediates the accompanying arteriolar dysfunction and platelet adhesion. METHODS AND RESULTS Intravital videomicroscopy was used to quantify arteriolar responses to acetylcholine, and leukocyte and platelet adhesion in postcapillary venules of wild-type (WT), immunodeficient (SCID), and IFN-gamma(-/-) mice on a normal (ND) or high-cholesterol (HC) diet. Acetylcholine-induced arteriolar dilation was impaired in WT-HC, compared with WT-ND. This endothelial dysfunction was absent in SCID-HC or IFN-gamma(-/-)-HC mice. Vasodilation was impaired by transfer of WT, but not IFN-gamma(-/-), T-cells to these immunodeficient mice. WT-HC mice exhibited elevated leukocyte and platelet adhesion in venules, versus WT-ND. This blood cell recruitment was attenuated to ND levels in SCID-HC and IFN-gamma(-/-)-HC mice, but restored to WT-HC levels by transfer of WT, but not IFN-gamma(-/-), T-lymphocytes. CONCLUSIONS These data reveal a novel role of T-lymphocyte-derived IFN-gamma in the development of endothelial dysfunction in arterioles during hypercholesterolemia and extend our previous observations that IFN-gamma mediates both inflammatory and thrombogenic responses to hypercholesterolemia in postcapillary venules.